Consumption of unregulated food items (false morels) and risk for neurodegenerative disease (amyotrophic lateral sclerosis)

Free Radicals ◽

Environmental Factors ◽

Strong Evidence ◽

Western Europe ◽

World War ◽

Food Items ◽

Sporadic Als ◽

Unknown environmental factors are thought to contribute to the etiology of sporadic forms of amyotrophic lateral sclerosis (ALS). Strong evidence supporting this view is found in the post-World War decline and disappearance of highincidence ALS in three Western Pacific populations that formerly utilized neurotoxic cycad seed as a traditional source of food and/or medicine. The principal toxins in cycads (cycasin) and in False Morel mushrooms (gyromitrin) generate methyl free radicals that damage DNA and cause mutation and uncontrolled division of cycling cells and degeneration of late-/postmitotic neurons. Since False Morels are scavenged for food in Finland, Russia, Spain, and USA, research studies are underway in Western Europe and USA to determine if the practice is associated with sporadic ALS.

Consumption of unregulated food items (false morels) and risk for neurodegenerative disease (amyotrophic lateral sclerosis)

Health Risk Analysis ◽

10.21668/health.risk/2020.3.11 ◽

2020 ◽

pp. 94-99

Author(s):

P.S. Spencer ◽

Keyword(s):

Free Radicals ◽

Environmental Factors ◽

Strong Evidence ◽

Western Europe ◽

World War ◽

Food Items ◽

Sporadic Als ◽

p62 overexpression induces TDP-43 cytoplasmic mislocalisation, aggregation and cleavage and neuronal death

Scientific Reports ◽

10.1038/s41598-021-90822-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

A. D. Foster ◽

L. L. Flynn ◽

C. Cluning ◽

F. Cheng ◽

J. M. Davidson ◽

...

Keyword(s):

Environmental Factors ◽

Neuronal Death ◽

Frontotemporal Lobar Degeneration ◽

Proteasome Inhibition ◽

Neuron Death ◽

AbstractAmyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) that exist on a spectrum of neurodegenerative disease. A hallmark of pathology is cytoplasmic TDP-43 aggregates within neurons, observed in 97% of ALS cases and ~ 50% of FTLD cases. This mislocalisation from the nucleus into the cytoplasm and TDP-43 cleavage are associated with pathology, however, the drivers of these changes are unknown. p62 is invariably also present within these aggregates. We show that p62 overexpression causes TDP-43 mislocalisation into cytoplasmic aggregates, and aberrant TDP-43 cleavage that was dependent on both the PB1 and ubiquitin-associated (UBA) domains of p62. We further show that p62 overexpression induces neuron death. We found that stressors (proteasome inhibition and arsenic) increased p62 expression and that this shifted the nuclear:cytoplasmic TDP-43 ratio. Overall, our study suggests that environmental factors that increase p62 may thereby contribute to TDP-43 pathology in ALS and FTLD.

Sterol auto-oxidation adversely affects human motor neuron viability and is a neuropathological feature of amyotrophic lateral sclerosis

Scientific Reports ◽

10.1038/s41598-020-80378-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

James C. Dodge ◽

Jinlong Yu ◽

S. Pablo Sardi ◽

Lamya S. Shihabuddin

Keyword(s):

Motor Neuron ◽

Cholesterol Homeostasis ◽

Cholesterol Oxidation ◽

Therapeutic Approaches ◽

Cellular Survival ◽

Sporadic Als ◽

Human Motor ◽

Als Patients ◽

AbstractAberrant cholesterol homeostasis is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease that is due to motor neuron (MN) death. Cellular toxicity from excess cholesterol is averted when it is enzymatically oxidized to oxysterols and bile acids (BAs) to promote its removal. In contrast, the auto oxidation of excess cholesterol is often detrimental to cellular survival. Although oxidized metabolites of cholesterol are altered in the blood and CSF of ALS patients, it is unknown if increased cholesterol oxidation occurs in the SC during ALS, and if exposure to oxidized cholesterol metabolites affects human MN viability. Here, we show that in the SOD1G93A mouse model of ALS that several oxysterols, BAs and auto oxidized sterols are increased in the lumbar SC, plasma, and feces during disease. Similar changes in cholesterol oxidation were found in the cervical SC of sporadic ALS patients. Notably, auto-oxidized sterols, but not oxysterols and BAs, were toxic to iPSC derived human MNs. Thus, increased cholesterol oxidation is a manifestation of ALS and non-regulated sterol oxidation likely contributes to MN death. Developing therapeutic approaches to restore cholesterol homeostasis in the SC may lead to a treatment for ALS.

Mitophagy Modulation, a New Player in the Race against ALS

International Journal of Molecular Sciences ◽

10.3390/ijms22020740 ◽

2021 ◽

Vol 22 (2) ◽

pp. 740

Author(s):

Enrique Madruga ◽

Inés Maestro ◽

Ana Martínez

Keyword(s):

Protein Aggregation ◽

Effective Treatment ◽

Unknown Etiology ◽

Drug Candidates ◽

Relevant Evidence ◽

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease that usually results in respiratory paralysis in an interval of 2 to 4 years. ALS shows a multifactorial pathogenesis with an unknown etiology, and currently lacks an effective treatment. The vast majority of patients exhibit protein aggregation and a dysfunctional mitochondrial accumulation in their motoneurons. As a result, autophagy and mitophagy modulators may be interesting drug candidates that mitigate key pathological hallmarks of the disease. This work reviews the most relevant evidence that correlate mitophagy defects and ALS, and discusses the possibility of considering mitophagy as an interesting target in the search for an effective treatment for ALS.

Glutathione S-transferase Omega 2 DD genotype is associated with an increased risk of sporadic amyotrophic lateral sclerosis in Chinese men

Journal of International Medical Research ◽

10.1177/03000605211033219 ◽

2021 ◽

Vol 49 (7) ◽

pp. 030006052110332

Author(s):

Zhiliang Fan ◽

Hong Jiang ◽

Xueqin Song ◽

Yansu Guo ◽

Xinying Tian

Keyword(s):

Healthy Subjects ◽

Chinese Population ◽

Sporadic Amyotrophic Lateral Sclerosis ◽

Glutathione S Transferase ◽

Genotype Frequencies ◽

Sporadic Als ◽

Increased Risk ◽

Chi Squared ◽

Objective To investigate whether GSTA1, GSTO2, and GSTZ1 are relevant to an increased risk of amyotrophic lateral sclerosis (ALS) in a Chinese population. Methods In this study, 143 sporadic ALS (sALS) patients (83 men, 60 women) and 210 age- and sex-matched healthy subjects were enrolled. Blood samples were collected by venipuncture. Genomic DNA was isolated by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) according to the manufacturer’s instructions. The potential associations between ALS and GSTA1, GSTO2, and GSTZ1 polymorphisms were estimated using chi-squared analysis and unconditional logistic regression. Results The D allele and genotype frequencies of GSTO2 were increased in sALS patients compared with healthy subjects, indicating that the GSTO2 DD genotype was associated with an increased risk of sALS (odds ratio [OR] = 3.294, 95% confidence interval [CI] = 1.039–10.448). However, a significant association between the DD genotype and the risk of sALS was evident in men only (OR = 7.167, 95% CI = 1.381–37.202). Conclusion This study revealed that the D allele and genotype frequencies of GSTO2 were increased in sALS patients. The GSTO2 DD genotype was associated with an increased risk of sALS in men in a Chinese population.

Role of Oxidative Stress in the Pathogenesis of Amyotrophic Lateral Sclerosis: Antioxidant Metalloenzymes and Therapeutic Strategies

Biomolecules ◽

10.3390/biom11030437 ◽

2021 ◽

Vol 11 (3) ◽

pp. 437

Author(s):

Pavlína Hemerková ◽

Martin Vališ

Keyword(s):

Oxidative Stress ◽

Antioxidant Enzymes ◽

Oxygen Radicals ◽

Clinical Symptoms ◽

Free Oxygen Radicals ◽

Free Oxygen ◽

Sporadic Als ◽

Familial Form ◽

Amyotrophic lateral sclerosis (ALS) affects motor neurons in the cerebral cortex, brainstem and spinal cord and leads to death due to respiratory failure within three to five years. Although the clinical symptoms of this disease were first described in 1869 and it is the most common motor neuron disease and the most common neurodegenerative disease in middle-aged individuals, the exact etiopathogenesis of ALS remains unclear and it remains incurable. However, free oxygen radicals (i.e., molecules containing one or more free electrons) are known to contribute to the pathogenesis of this disease as they very readily bind intracellular structures, leading to functional impairment. Antioxidant enzymes, which are often metalloenzymes, inactivate free oxygen radicals by converting them into a less harmful substance. One of the most important antioxidant enzymes is Cu2+Zn2+ superoxide dismutase (SOD1), which is mutated in 20% of cases of the familial form of ALS (fALS) and up to 7% of sporadic ALS (sALS) cases. In addition, the proper functioning of catalase and glutathione peroxidase (GPx) is essential for antioxidant protection. In this review article, we focus on the mechanisms through which these enzymes are involved in the antioxidant response to oxidative stress and thus the pathogenesis of ALS and their potential as therapeutic targets.

Amyotrophic lateral sclerosis and environmental factors

Functional Neurology ◽

10.11138/fneur/2016.31.1.007 ◽

2016 ◽

Cited By ~ 14

Author(s):

Virginia Bozzoni

Keyword(s):

Environmental Factors ◽

Revealing the Mutational Spectrum in Southern Africans With Amyotrophic Lateral Sclerosis

Neurology Genetics ◽

10.1212/nxg.0000000000000654 ◽

2022 ◽

Vol 8 (1) ◽

pp. e654

Author(s):

Melissa Nel ◽

Amokelani C. Mahungu ◽

Nomakhosazana Monnakgotla ◽

Gerrit R. Botha ◽

Nicola J. Mulder ◽

...

Keyword(s):

Population Group ◽

Genetic Ancestry ◽

Familial Case ◽

Data Sets ◽

Variant Of Uncertain Significance ◽

Pathogenic Variants ◽

Sporadic Als ◽

Uncertain Significance ◽

Background and ObjectivesTo perform the first screen of 44 amyotrophic lateral sclerosis (ALS) genes in a cohort of African genetic ancestry individuals with ALS using whole-genome sequencing (WGS) data.MethodsOne hundred three consecutive cases with probable/definite ALS (using the revised El Escorial criteria), and self-categorized as African genetic ancestry, underwent WGS using various Illumina platforms. As population controls, 238 samples from various African WGS data sets were included. Our analysis was restricted to 44 ALS genes, which were curated for rare sequence variants and classified according to the American College of Medical Genetics guidelines as likely benign, uncertain significance, likely pathogenic, or pathogenic variants.ResultsThirteen percent of 103 ALS cases harbored pathogenic variants; 5 different SOD1 variants (N87S, G94D, I114T, L145S, and L145F) in 5 individuals (5%, 1 familial case), pathogenic C9orf72 repeat expansions in 7 individuals (7%, 1 familial case) and a likely pathogenic ANXA11 (G38R) variant in 1 individual. Thirty individuals (29%) harbored ≥1 variant of uncertain significance; 10 of these variants had limited pathogenic evidence, although this was insufficient to permit confident classification as pathogenic.DiscussionOur findings show that known ALS genes can be expected to identify a genetic cause of disease in >11% of sporadic ALS cases of African genetic ancestry. Similar to European cohorts, the 2 most frequent genes harboring pathogenic variants in this population group are C9orf72 and SOD1.

Sensory cortex hyperexcitability predicts short survival in amyotrophic lateral sclerosis

Neurology ◽

10.1212/wnl.0000000000005424 ◽

2018 ◽

Vol 90 (18) ◽

pp. e1578-e1587 ◽

Cited By ~ 8

Author(s):

Toshio Shimizu ◽

Kota Bokuda ◽

Hideki Kimura ◽

Tsutomu Kamiyama ◽

Yuki Nakayama ◽

...

Keyword(s):

Multivariate Analysis ◽

Action Potential ◽

Median Nerve ◽

Rating Scale ◽

Sensory Cortex ◽

Peak Amplitude ◽

Short Survival ◽

Sporadic Als ◽

ObjectiveTo investigate somatosensory cortex excitability and its relationship to survival prognosis in patients with amyotrophic lateral sclerosis (ALS).MethodsA total of 145 patients with sporadic ALS and 73 healthy control participants were studied. We recorded compound muscle action potential and sensory nerve action potential of the median nerve and the median nerve somatosensory evoked potential (SEP), and we measured parameters, including onset-to-peak amplitude of N13 and N20 and peak-to-peak amplitude between N20 and P25 (N20p-P25p). Clinical prognostic factors, including ALS Functional Rating Scale–Revised, were evaluated. We followed up patients until the endpoints (death or tracheostomy) and analyzed factors associated with survival using multivariate analysis in the Cox proportional hazard model.ResultsCompared to controls, patients with ALS showed a larger amplitude of N20p-P25p in the median nerve SEP. Median survival time after examination was shorter in patients with N20p-P25p ≥8 μV (0.82 years) than in those with N20p-P25p <8 μV (1.68 years, p = 0.0002, log-rank test). Multivariate analysis identified a larger N20p-P25p amplitude as a factor that was independently associated with shorter survival (p = 0.002).ConclusionSensory cortex hyperexcitability predicts short survival in patients with ALS.

A-151 Cognitive Impairment in Amyotrophic Lateral Sclerosis

Archives of Clinical Neuropsychology ◽

10.1093/arclin/acab062.169 ◽

2021 ◽

Vol 36 (6) ◽

pp. 1205-1205

Author(s):

Etiane Navarro ◽

Charles J Golden

Keyword(s):

Cognitive Impairment ◽

Literature Review ◽

Cognitive Impairments ◽

Empirical Literature ◽

Sporadic Als ◽

Neuropsychological Assessments ◽

Familial Als ◽

Als Patients ◽

Abstract Objective Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease caused by degeneration of the upper and lower motor neurons. This literature review examines the recurring etiology of cognitive impairments in ALS through empirical literature. The current study explores ALS across different subtypes and potential cognitive impairments. Two classifications are primarily examined ALS, and ALS with frontotemporal dementia (ALS-FTD). Involving three categories: familial inheritance pattern, genetic mutation, or sporadic. Neuropsychological studies affirm cognitive impairments in individuals diagnosed with ALS and ALS-FTD. Data Selection Data was culled from the American Psychological Association (PsycInfo), PubMed, Google Scholar. Terms used in this literature review include cognitive impairment in ALS and ALS-FTD, executive function deficiencies in ALS, neuropsychology in ALS, neuropsychological deficits in ALS, neuropsychological assessments for ALS, cognitive impairments in familial ALS, genetic ALS, and sporadic ALS, familial ALS, sporadic ALS, genetic mutations involved in ALS. Search dates December 20–23 of 2020 and March 3–4 of 2021. A total of 40 studies were examined. Data Synthesis ALS-patients demonstrate a significant cognitive impairment. However, influencing comorbidities accompanying the disease may be contributing to these impairments. Researchers employed neuroimaging and neuropsychological batteries to further understand influencing factors involved in ALS and cognition. Conclusions Researchers now understand ALS as a multi-symptomatic disorder and acknowledge the presence of cognitive impairments at various encased levels. There are limitations in neuropsychological batteries that accommodate for executive dysfunctions observed in ALS patients. Future studies should explore neuropsychological assessments that accommodate for motor deficits and dysarthria when assessing cognitive impairment in ALS patients.